Patients with atherosclerotic heart disease frequently develop new or enlarge existing coronary collateral vessels. These vessels supply the region of myocardium distal to the occluded vessel and may protect the heart from infarction. However, they generally do not supply sufficient blood flow to prevent ischemia during periods of augmented myocardial oxygen demands. The purpose of the proposed research is to further develop a model of the coronary collateral circulation and to examine various mechanisms that may enhance or retard development of this circulation and capillary density. The pig provides a model of the coronary collateral circulation in which there is minimal (5%) infarction but limited development of collateral vessels. Thus, function of the collateralized myocardium is normal at rest but markedly reduced during exercise. In preliminary studies we have demonstrated that collateral blood flow and regional function are improved without an increased extent of infarction after a month of physical conditioning. In the proposed studies we will examine left circumflex ameroid-constricted pigs at rest, and during exercise 7, 11 and 16 weeks post-instrumentation. Initially, to further develop this model and assess its relevance to humans with atherosclerosis, we will determine the effects of microsphere entrapment; animal age (i.e. maturity) and the effect of more prolonged constriction on the development of coronary collateral vessels. We next will examine the response of the collateral circulation to two intensities of more prolonged exercise training, beta-adrenoceptor blockade and beta- adrenoceptor blockade with exercise training. To dissect out some of the chemical and mechanical stimuli associated with exercise that may promote collateral and capillary vessel growth, pigs will be studied during and after chronic bradycardiac pacing, adenosine infusion (mechanical stimulation) and cyclooxygenase inhibition (to decrease prostaglandin production) and chronic PGE2 administration (chemical stimulation). We predict that exercise training, bradycardiac pacing, adenosine infusion, and PGE2 administration will enhance global function of the left ventricle during exercise. Conversely, beta-adrenoceptor blockade and cyclooxygenase inhibition will limit the development of collateral vessels and reduce the improvement observed with exercise training. Therefore, these studies will yield evidence about exercise training and some of the chemical and mechanical mechanisms regulating growth of collateral and capillary vessels. These studies may suggest therapeutic strategies that could help with management of patient with critical atherosclerotic heart disease.